Subfertility impacts >1.25 million men annually, although many ejaculate reasonable numbers of motile and normal sperm. Project goal is low-cost therapy to increase probability of pregnancy via IUI. We hypothesize some infertile men have insufficient UPSEBP (universal primary sperm-egg binding protein) on their sperm. Synthetic peptide, based on presumed sequence of human UPSEBP, increased binding of human sperm to a zona-like substrate for 46% of 28 samples of fresh patient semen. The innovative peptide sequence increased fertility with 4 model species (e.g., by 14 percentage units after IUI of cattle; equal to or >13 units in IVF for cattle and mice). Specific Aims are: (1) determine amino acid sequence of UPSEBP in human seminal plasma; and (2) establish range in amount of endogenous UPSEBP in seminal plasma from patients and fertile men. Measurement of UPSEBP in semen from patients and fertile men should show that the problem is real. Isolation and sequencing of human UPSEBP will allow the synthetic molecule to conform with the natural sequence, and classification as a biologic. Completion will allow evaluation of efficacy of synthetic peptide to increase binding of patient sperm to human zona pellucida or similar synthetic substrates (Phase-II) , and clinical trials using IUI or IVF (Phase-III).